Therapeutic compositions based on 1,2-dithiole-3-thione derivatives

ABSTRACT

The present invention relates to therapeutic compositions based on compounds chosen from the formulae: ##STR1## in which: X is chosen from ═S, ═O, ═SO, ═N--OH, ═N--R 5 , ═N--NH--CONH 2 , ═N--NH--CSNH 2  and ##STR2## A is chosen from the ##STR3##  group, a group of formula ##STR4##  a C═O group, a group C═N--R 4  and a CHOH group, and their pharmaceutically acceptable salts. 
     These compositions may be used as free-radical trapping agents.

This Application is a 371 of PCT/FR92/00392 filed Apr. 30, 1992.

The present invention relates to therapeutic compositions based on1,2-dithiole-3-thione derivatives.

As prior art, there may be mentioned anethole trithione or5-(p-methoxyphenyl)-3H-1,2-dithiole-3-thione which is used in therapy asa choleretic (U.S. Pat. No. 2,556,963), and compounds of formula:##STR5## described by Ebel et al., (Bull. Soc. Chim. Fr. 1963, 161), thecompound A being obtained by reaction of sulphur with isophorone and thecompound B being obtained from the compound A by reaction with NH₂ OH.

Teicher et al. (Br. J. Cancer, 1990, 62, 17) disclose the use of1,2-dithiole-3-thiones and in particular5-(2-thienyl)-1,2-dithiole-3-thione as radioprotectors.

The subject of the present invention is therapeutic compositionscontaining, as active principle, a compound chosen from compounds offormulae: ##STR6## in which X is-chosen from ═S, ═O, ═N--OH, ═N--R₅, R₅being a C₁ -C₆ alkyl or an aryl group, ═N--NH--CO--NH₂ and═N--NH--CS--NH₂, and ##STR7## Z and Z' being electron-attracting groupssuch as ester or cyano groups,

A is chosen from a ##STR8## a group of formula ##STR9## (where R₃ ischosen from a C₁ -C₆ alkyl group, a C₁ -C₆ alkyl group substituted withone more groups chosen from hydroxyl, amino, chloro and C₁ -C₄ alkoxygroups, an aryl (C₁ -C₆ alkyl) group, a (C₁ -C₆ alkyl) carbonyl groupand an aryl (C₁ -C₆ alkyl)carbonyl group),

a ##STR10## R₄ being a C₁ -C₆ alkyl group or an aryl group, and a CHOHgroup,

R₁ and R₂ are chosen, independently of one another, from hydrogen, ahalogen, a nitro group, a nitroso group, a thiocyano group, a C₁ -C₆alkyl group, a C₂ -C₆ alkenyl group, an aryl group, an aryl(C₁ -C₆alkyl) group, an aryl(C₂ -C₆ alkenyl) group, a carboxyl group, a (C₁ -C₆alkyl)carbonyl group, an arylcarbonyl group, a (C₁ -C₆ alkoxy)carbonylgroup, a (C₁ -C₆ alkoxy)carbonyl(C₁ -C₆ alkyl) group, a C₁ -C₆ alkoxygroup, a trifluoromethyl group, an amino group, a di(C₁ -C₆alkyl)amino(C₁ -C₆ alkyl) group, an acylamino group of formula--NHCOC_(n) H_(2n+1) with n from 0 to 6, a group --NH--CSC_(n) H_(2n+1)with n from 0 to 6, a terpenyl group, a cyano group, a C₂ -C₆ alkynylgroup, a C₂ -C₆ alkynyl group substituted with a C₁ -C₆ alkyl or an arylgroup, a hydroxy(C₁ -C₆ alkyl) group, a (C₁ -C₆ acyl)-oxy(C₁ -C₆ alkyl)group, a (C₁ -C₆ alkyl)thio group and an arylthio group,

or alternatively R₁ and R₂ together form a mono- or polycyclic C₂ -C₂₀alkylene group optionally comprising one or more hetero atoms, with theexception of the 2,2-dimethyltrimethylene group, or a C₃ -C₁₂cycloalkylene group,

R is chosen from a C₁ -C₆ alkyl group,

Y⁻ is a pharmaceutically acceptable anion such as halide or sulphate,

and their pharmaceutically acceptable salts.

The present invention relates in particular to a pharmaceuticalcomposition comprising, as active ingredient, a compound chosen from thecompounds of formulae: ##STR11## in which: X is chosen from S and O,

A is chosen from a ##STR12## a group of formula ##STR13## (where R₃ ischosen from a C₁ -C₆ alkyl group, a C₁ -C₆ alkyl group substituted withone more groups chosen from hydroxyl, amino, chloro and C₁ -C₆ alkoxygroups, an aryl(C₁ -C₆ alkyl) group, a (C₁ -C₆ alkyl)carbonyl group andan aryl (C₁ -C₆ alkyl)carbonyl group),

a C═O group, a ##STR14## R₄ being a C₁ -C₆ alkyl group or an aryl group,and a CHOH group,

R₁ and R₂ are chosen, independently of one another, from hydrogen, ahalogen, a C₁ -C₆ alkyl group, an aryl group, an aryl (C₁ -C₆ alkyl)group, a carboxyl group, an alkoxycarbonyl group, a C₁ -C₆ alkoxy group,a trifluoromethyl group, a di(C₁ -C₆ alkyl)amino(C₁ -C₆ alkyl) group andan acylamino group of formula --NHCOC_(n) H_(2n+1) with n from 0 to 6,or alternatively R₁ and R₂ together form a C₂ -C₁₂ alkylene group, withthe exception of the 2,2-dimethyltrimethylene group, or a C₃ -C₁₂cycloalkylene group,

R is chosen from a C₁ -C₆ alkyl group,

and their pharmaceutically acceptable salts.

In the foregoing definition, aryl group or aryl fraction of an arylalkylgroup denotes an aromatic carbon-based group such as a phenyl ornaphthyl group or an aromatic heterocyclic group such as a thienyl orfuryl group, it being possible for these groups to bear one or moresubstituents chosen from a halogen atom, a C₁ -C₄ alkyl group, a C₁ -C₄alkoxy group, a trifluoromethyl group, a nitro group and a hydroxylgroup.

Some of the compounds of formula I are known.

Thus, Stachel et al. (Arch. Pharm. 1991, 324, 2, 131) describe1,2-dithiole-3-thiones of formula I in which A═CO, X═S, R₁ ═OCH₃ and R₂═OCH₃ or NH₂.

Faust et al., (Z Chem., 1967, 7, 7, 275) describe compounds of formula Iin which A═CO, R₁ ═H, X═S and R₂ ═Cl, OC₂ H₅, NH₂ or X═O and R₂ ═Cl, OC₂H₅, NH₂, NHC₆ H₅.

In addition, J. Fabian et al. (Chem. Ind. 966, 1962-3) disclose a1,2-dithiole-3-thione having the formula I in which X═S, AR₂ ═CO--OC₂ H₅and R₁ ═H.

Trebaul (Bul. Soc. Chim., 1973, 2, 2, 721) describes compounds offormula I in which A═CO, R₁ ═C₆ H₅, X═S and R₂ ═OC₂ H₅, NH₂, N(C₆ H₅)₂or X═O and R₂ ═OC₂ H₅, Cl, p-OCH₃ C₆ H₄, NH₂, NHC₆ H₅, N(C₆ H₅)₂.

Moreover, a few compounds of formula I in which A══N--Ar and X═S aredescribed by Quiniou (Bul. Soc. Chem., 1960, 5, 47) and in U.S. Pat. No.4,190,727.

A first group of compounds of formula I is formed by those in which A isa ##STR15## that is to say oximes of formula ##STR16##

These compounds, which are new, may be prepared according to theinvention from 1,2-dithiole-3-thiones of formula: ##STR17## by theaction of nitrous acid or isoamyl nitrite.

In practice, a compound of formula III may be reacted with sodiumnitrite in a glacial acetic acid medium at approximately 40° C., orisoamyl nitrite in the presence of sodium ethylate in an ethanol mediumat 0° C. or at room temperature.

A number of compounds of formula III are known. The others may beprepared according to known processes (see, in particular, Thuillier A.,Vialle J., Bull. Soc. Chim. Fr., 1962, 2187, Legrand L., Lozach N.,Bull. Soc. Chim. Fr., 1955, 79).

It should be noted that the reaction of sodium nitrite in a glacialacetic acid medium with the compounds of formula III generally leads notonly to the formation of the oximes of formula II, but also to theformation of compounds of formula: ##STR18## which constituteintermediate products and which yield the oximes of formula II by theaction of sodium hydroxide, and also, possibly, of the compounds offormula ##STR19## which constitute by-products.

It should also be noted that the reaction of isoamyl nitrite with thecompounds of formula III leads only to the formation of oximes offormula II.

A second group of compounds of formula I is formed by those in which Ais a ##STR20## that is to say aldehydes or ketones of formula ##STR21##

These compounds of formula VI may be prepared by reaction offormaldehyde in an acid medium with an oxime of formula II.

Some of the compounds of formula VI are new. This applies, inparticular, to the compounds VIa, corresponding to the formula VI but inwhich R₁ is an alkyl or arylalkyl group or a halogen atom, to thecompounds VIb, corresponding to the formula VI but in which R₁ is anaryl group and R₂ is a hydrogen atom or an alkyl group, and to thecompounds VIc, corresponding to the formula VI but in which R₁ is ahydrogen atom and R₂ is an alkyl group.

A third group of compounds of formula I is formed by those in which A isa group C═N--OR' where R'₃ is an optionally substituted C₁ -C₆ alkylgroup, in particular substituted with one or more groups chosen fromhydroxyl, amino, chloro and C₁ -C₄ alkoxy groups, or an aryl (C₁ -C₆alkyl) group, that is to say compounds of formula ##STR22##

These compounds may be obtained by alkylation of an oxime of formula IIusing a halide R'₃ -Hal in the presence of sodium ethylate.

It has, moreover, been discovered that, if an alkylation of an oxime offormula II is performed with a halide R'₃ -Hal but in the presence of anaqueous sodium hydroxide solution, compounds of formula ##STR23## inwhich R'₃ has the meaning given above, are obtained instead of compoundsof formula VII.

It is possible to explain the production of the compounds obtained underthese conditions by the fact that the oximes of formula II possess atautomeric thiol form: ##STR24##

A fourth group of compounds of formula I is formed by the compounds inwhich A is a group C═N--O--CO--R"₃, R"₃ being chosen from a hydrogenatom, an optionally substituted C₁ -C₆ alkyl group, an aryl group and anaryl(C₁ -C₆ alkyl) group, that is to say compounds of formula ##STR25##in which R"₃ has the meaning given above.

These compounds may be obtained by acylation of an oxime of formula IIwith an acid chloride R"₃ COCl in a toluene medium in the presence ofpyridine.

A fifth group of compounds of formula I is formed by the compounds inwhich A is a CH--OH group, that is to say the compounds of formula##STR26##

These compounds may generally be obtained by reduction of a compound offormula VI.

A sixth group of compounds of formula I is formed by the compounds inwhich A is a group C═N--R₄, R₄ being a C₁ -C₆ alkyl or an aryl group,that is to say compounds of formula ##STR27##

These compounds may be obtained from the compounds of formula VI by theaction of amine of formula R₄ --NH₂.

A seventh group of compounds of formula I is formed by the compounds inwhich A is a C═O group and X is an oxygen atom, that is to say compoundsof formula: ##STR28## in which R₁ and R₂ have the meaning given above.These compounds may be obtained from the compounds of formula VI by theaction of benzonitrile oxide.

More generally, the compounds of formula I in which X═O may be obtainedfrom the compounds of formula I in which X═S by the action ofbenzonitrile oxide.

The oximes of formula VI can, in addition, react in the cold state withmethyl acetylenedicarboxylate in acetone solution according to Davy andDecrouen (Bull. Soc. Chim., 1976, 115) to give compounds of formula##STR29##

The compounds of formula Ia may be obtained from the compounds offormula I by reaction with an alkyl iodide of formula RI, R being a C₁-C₆ alkyl group.

The examples which follow illustrate the present invention.

I--Preparation of the oximes of formula II, the disulphides of formula Vand the oxadithiazapentalenes of formula IV

1--Use of sodium nitrite in a glacial acetic acid medium.

EXAMPLE

In a 250-ml Erlenmeyer flask equipped with a magnetic stirrer, 1 g of4,5-dimethyl-1,2-dithiole-3-thione is dissolved in 30 ml of glacialacetic acid brought to the boil. The mixture is allowed to cool to 40°C. 2 g of sodium nitrite in the solid state are added in small portions.An ochre precipitate forms immediately. After 30 min, the acetic acidsolution is diluted with water. The copious precipitate, consistingessentially of the disulphide of formula V and traces of the starting1,2-dithiole-3-thione, is filtered off. The precipitate is added to 20%sodium hydroxide solution. After stirring at 60° C. for 2 hours, almostcomplete dissolution has taken place with a change in colour. Theaqueous solution becomes dark brown. It is extracted with toluene and isthen acidified with cooling. A precipitate of the crude, orange-yellowoxime appears. The remaining, unprecipitated oxime is extracted eitherwith sulphuric ether solution or with a dichloromethane solutioncontaining 5% of acetone.

Furthermore, the acetic acid solution obtained after filtering off thecrude oxime is extracted with a toluene solution which is combined withthat used for extraction of the sodium hydroxide phase. The toluenesolution is washed with water, dried over sodium sulphate, concentratedand chromatographed on silica gel. The oxadithiazapentalene is elutedafter the starting dithiolethione with toluene.

The structure of the oximes of formula II is determined from a study ofthe ¹ H and ¹³ C NMR, IR and mass spectra and from the microanalyses.Assignment of the syn and anti structures for the oxime whosepreparation is described above is performed on the basis of the valuesof the coupling constants J¹ (C-H) in the arrangements below: ##STR30##

The characteristics of the products obtained, as well as those of otherproducts of formulae II, IV and V, are collated in Tables I and II.

                                      TABLE I                                     __________________________________________________________________________                              Oxadithiaza-                                                   Oximes of      pentalenes of                                                  formula II     formula IV                                          R.sub.1                                                                           R.sub.2                                                                              Code                                                                             Yld %  M.p. °C.                                                                    Code                                                                             Yld %                                                                             M.p. °C.                              __________________________________________________________________________    CH.sub.3                                                                          H      1  65syn(P*) +                                                                          174  21 30  117                                                        anti                                                            CH.sub.3                                                                          CH.sub.3                                                                             2  50syn(P*)                                                                            138  22 40  120                                                        anti                                                            H   H      2  20     143  23 10   83                                          H   C.sub.6 H.sub.5                                                                      4  30     165  24 15  118                                          OCH.sub.3                                                                         H      5  30     108                                                      H          6  20     142                                                          H      7  15     139                                                      H   CH.sub.3                                                                             8  55     181  25 30   93                                          C.sub.2 H.sub.5                                                                   CH.sub.3                                                                             9  50      92  26 20   90                                          CH.sub.3                                                                          CH.sub.3 CHCH.sub.3                                                                  10 45     113  27 30  160                                          __________________________________________________________________________     (*)P: preponderant                                                       

                                      TABLE II                                    __________________________________________________________________________               Oximes of    Dimers of                                                        formula II   formula V                                             R.sub.1                                                                             R.sub.2                                                                            Code                                                                              Yld %                                                                             M.p. °C.                                                                    Code                                                                              Yld %                                                                             M.p. °C.                               __________________________________________________________________________    --(CH.sub.2).sub.3                                                                       11  50  195  31  25  120-21                                        C.sub.6 H.sub.5                                                                     CH.sub.3                                                                           12  55  163  32  25  181-82                                        C.sub.6 H.sub.5                                                                     C.sub.6 H.sub.5                                                                    13  20  171  33  30  190-91                                        COOC.sub.2 H.sub.5                                                                  C.sub.6 H.sub.5                                                                    14  40  194  34  25  163-64                                        CH.sub.2 C.sub.6 H.sub.5                                                            H    15  80  143  35  15  106-8                                         CH.sub.2 C.sub.6 H.sub.5                                                            CH.sub.3                                                                           16  50  122                                                        H     C.sub.2 H.sub.5                                                                    17  55  130  36  30   143-155                                      C.sub.6 H.sub.5                                                                     CH.sub.2 C.sub.6 H.sub.5                                                           18  40  157  37  20   102-103                                      C.sub.2 H.sub.5                                                                     H    19  50  149-160                                                    Cl    H    20  45  230                                                        __________________________________________________________________________

2--Use of isoamyl nitrite.

Example

An ethanolic solution of 5-methyl-1,2-dithiole-3-thione (1 equivalent)is added in the course of 1/2 hour with an equivalent amount of isoamylnitrite at room temperature to an ethanolic solution containing twoequivalents of sodium ethylate. The mixture is left stirring overnight.It is poured into water and the oxime (compound 3) is extracted with anethyl ether solution. The ethereal solution is washed with water, driedover sodium sulphate, concentrated and purified by chromatography onsilica gel. The oxime is eluted after the starting dithiolethione,approximately 40% of the initial amount of which is recovered.

II--Preparation of the compounds of formula VI

Example

2 g of dithiolethione oxime of formula II are brought into contact with25 ml of 37% aqueous formaldehyde solution acidified with a few drops ofconcentrated hydrochloric acid and 100 ml of toluene. The mixture isbrought to reflux while stirring for 2 hours. The toluene solution verysoon becomes dark red.

After cooling and when settling has taken place, the toluene phase isseparated, washed with water to neutrality, dried over sodium sulphate,concentrated and chromatographed on silica gel. The dithiolethionealdehydes or ketones of formula VI are eluted with a 60:40 petroleumether/toluene mixture.

Their structures are established on the basis of conventional techniquesof structural analysis, including the use of elemental analysis. Inparticular, in IR spectroscopy, these compounds all display a ν_(c)═Oband. Their characteristics are given in Table III.

                  TABLE III                                                       ______________________________________                                        Code  R.sub.1   R.sub.2      M.p. °C.                                                                       ν.sub.c═o (cm.sup.-1)             ______________________________________                                        41    CH.sub.3  H            105     1660                                     42    C.sub.6 H.sub.5                                                                         H            132     1625                                     43    --CH.sub.2 --CH.sub.2 --CH.sub.2 --                                                               95       1670                                       44    CH.sub.3  CH.sub.3      76     1690                                     45    H         H            100     1670                                     46    C.sub.6 H.sub.5                                                                         CH.sub.3      86     1670                                     47    OCH.sub.3 H            101     1660                                     48    H         CH.sub.3     115     1660                                     49    CH.sub.2 C.sub.6 H.sub.5                                                                H            124     1665                                     50    C.sub.2 H.sub.5                                                                         CH.sub.3     125     1670                                     51    CH.sub.3  CH.sub.3 --CH--CH.sub.3                                                                     59     1690                                     52    CH.sub.2 C.sub.6 H.sub.5                                                                CH.sub.3      63     1670                                     53    H         CH.sub.2 --CH.sub.3                                                                        116     1680                                     54    C.sub.2 H.sub.5                                                                         H            75-76   1675                                     55    Cl        H            136     1680                                     ______________________________________                                    

III--Preparation of the compounds of formula VII

1 equivalent of the oxime II 1 in ethanolic solution is added in thecourse of 1/2 hour to an ethanolic solution containing 2 equivalents ofsodium ethylate while cooling externally with a bath of ice-cold water.1.1 equivalents of methyl iodide are then added. The mixture is leftstirring at room temperature for about 15 hours. The solution is thendiluted with water and extracted with toluene and the toluene solutionis dried over sodium sulphate and concentrated.

The residue is chromatographed on silica gel.

5-Methoxyiminomethyl-4-methyl-1,2-dithiole-3-thione (VII 1) is elutedwith a petroleum ether/toluene (90:10) mixture.

It is a red solid, m.p. 93°-94° C. ¹ H NMR (300 MHz) (CDCl₃) δ ppm/TMS=H(s:8.30); OCH₃ (s:4.10); CH₃ (s:2.30).

IV--Preparation of the compounds of formula VIII

The oxime II is dissolved in 10% aqueous sodium hydroxide solution; anexcess of methyl iodide is added in the cold state and the mixture isleft stirring at room temperature overnight.

It is then extracted with a toluene solution, which is washed withwater, dried, concentrated and chromatographed on silica gel.

The 5-(methylthio)oxadithiazapentalenes VIII are eluted with a petroleumether/toluene (60:40) mixture.

The characteristics of compounds of formula VIII are collated in TableIV.

                                      TABLE IV                                    __________________________________________________________________________                                  δppm/CDCl.sub.3                           Code                                                                              R.sub.1                                                                             R.sub.2  R'.sub.3                                                                            M.p. °C.                                                                    methylthio                                      __________________________________________________________________________    61  CH.sub.3                                                                            H        CH.sub.3                                                                            115  2.79                                            62  C.sub.6 H.sub.5                                                                     H        CH.sub.3                                                                            118  2.70                                            63  --CH.sub.2 --CH.sub.2 --CH.sub.2 --                                                          CH.sub.3                                                                            114  2.75                                            64  CH.sub.3                                                                            CH.sub.3 CH.sub.3                                                                            107  2.70                                            65  H     H        CH.sub.3                                                                            106  2.79                                            66  C.sub.6 H.sub.5                                                                     CH.sub.3 CH.sub.3                                                                            160  2.60                                            67  C.sub.6 H.sub.5                                                                     C.sub.6 H.sub.5                                                                        CH.sub.3                                                                            201  2.60                                            68  COOC.sub.2 H.sub.5                                                                  C.sub.6 H.sub.5                                                                        CH.sub.3                                                                            135  2.83                                            69  OCH.sub.3                                                                           H        CH.sub.3                                                                            109  2.68                                            70  H     CH.sub.3 CH.sub.3                                                                            109  2.73                                            71  CH.sub.2 C.sub.6 H.sub.5                                                            H        CH.sub.3                                                                            110  2.72                                            72  CH.sub.3 CH.sub.2                                                                   CH.sub.3 CH.sub.3                                                                            101  2.80                                            73  CH.sub.3                                                                            CH.sub.3 --CH--CH.sub.3                                                                CH.sub.3                                                                             99  2.80                                            74  C.sub.6 H.sub.5                                                                     CH.sub.3 CH.sub.3                                                                            119  2.64                                            75  H     CH.sub.2 --CH.sub.3                                                                    CH.sub.3                                                                             80  2.74                                            76  CH.sub.3                                                                            H        C.sub.2 H.sub.5                                                                     100-102                                                                            3.18                                            77  CH.sub.3                                                                            H        CH.sub.2 C.sub.6 H.sub.5                                                            136  4.38                                            __________________________________________________________________________

V--Preparation of the compounds of formula IX

1.1 equivalents of acetyl chloride are added to a toluene solutioncontaining 1 equivalent of dithiolethione oxime II and a few drops ofpyridine while cooling externally with a bath of ice-cold water.Stirring is maintained for 2 hours, the above solution is then pouredinto water and the product is extracted with toluene. The toluenesolution is then washed with water, dried over sodium sulphate, filteredand concentrated and the residue is chromatographed on silica gel. TheO-acyldithiolethione oximes IX are eluted with toluene.

The characteristics of the compounds of forumla IX are collated in TableV.

                  TABLE V                                                         ______________________________________                                        Code    R.sub.1  R.sub.2                                                                             R'.sub.3                                                                              Yield M.p. °C.                          ______________________________________                                        81      CH.sub.3 H     CH.sub.3                                                                              50%   127                                      82      C.sub.6 H.sub.5                                                                        H     CH.sub.3                                                                              55%   164                                      ______________________________________                                    

VI--Preparation of the compounds of formula X

1 g of 5-acetyl-4-methyl-1,2-dithiole-3-thione is dissolved in 150 cm³of absolute ethanol. The mixture is cooled externally with a bath ofice-cold water and an excess of cyanoborohydride is then added. Themixture is allowed to return to room temperature and stirring iscontinued for about ten hours.

The solution is concentrated to dryness. The residue is then taken upafter cooling with a few ml of dilute hydrochloric acid solution. Theprecipitate and the solution are treated with toluene. Thedithiolethione alcohol does not dissolve. It is purified bychromatography on silica gel. It is transferred to the column afterdissolution in the minimum amount of ethyl acetate; it is eluted with anethyl acetate/toluene (30:70) mixture.5-(1-Hydroxyethyl)-4-methyl-1,2-dithiole-3-thione is obtained in theform of light yellow crystals, m.p. 79°-80° C. (benzene).

VII--Preparation of the compounds of formula XI

An equimolar mixture of aniline and dithiolethione oxime II 1 is broughtto reflux for 3 hours in absolute ethanol. The solution blackensimmediately. The ethanolic solution is concentrated to dryness. Theresidue is chromatographed on silica gel.5-Phenyliminomethyl-4-methyl-1,2-dithiole-3-thione takes the form ofblack crystals, m.p. 124°-125° C. (petroleum ether).

VIII--Preparation of the compounds of formula XII

The procedure of BOBERG and KNOOP (LIEBIGS ANN. CHEM. 1967, 708, 148) isused:

1 g of 5-formyl-4-methyl-1,2-dithiolethione and 1 g of benzohydroxamoylchloride (G. W. Perold, A. P. Steyn and F. K. V. von Reiche, J. Am.Chem. Soc. 1957, 79, 462) are dissolved in a minimum amount of drytoluene. Triethylamine is added dropwise and with stirring until theformation of triethylamine hydrochloride is complete. During thisaddition, the mixture is maintained at room temperature. The initiallydark red solution becomes colourless. Stirring is continued for 3 h, thehydrochloride is then filtered off and the filtrate is concentrated todryness. The residue is taken up with 100 cc of xylene and the mixtureis brought to reflux for 3 h. It is concentrated to dryness; the residueis crystallised in methanol. 5-Formyl-4-methyl-1,2-dithiol-3-one is acolourless solid, m.p. 84° C., yld=65% (C═O KBr 1640 cm⁻¹).

IX--Preparation of the compounds of formula XIII

Equivalent amounts of 5-formyl-4-methyldithiolethione oxime and methylacetylenedicarboxylate are dissolved in the minimum amount of dryacetone. After the mixture has stood for about twenty hours, theaddition compound of formula XIII,3-(4,5-dimethoxycarbonyl-1,3-dithiol-2-ylidene)-2-thioxobutanal oxime,crystallises; it is filtered off and crystallised again in acetone; m.p.139° C., dark red crystals, IR: OH 3210 cm⁻¹ broad band; C═O 1720-1740cm⁻¹. ¹ HNMR (C₃ D₆ O) ppm: OH (s:10.68); H(CH) (s:8.42) CH₃ (s:2.82);CH₃ (COO CH₃) (s:3.92 and 4).

X--Preparation of the compounds of formula Ia

Example Preparation of 5-formyl-4-methyl-3-methylthio-1,2-dithiolyliumiodide

5-Formyl-4-methyl-1,2-dithiole-3-thione is dissolved in an excess ofmethyl iodide.

The mixture is left standing for several days; the dithiolylium ioncrystallises out.

The product is filtered off and recrystallised in benzene.

5-Formyl-4-methylthio-1,2-dithiolylium iodide, m.p. 140°-142° C., isthereby obtained.

XI--Preparation of the compounds of formula III

Example A Preparation of 5-ethyl-4-phenyl-1,2-dithiole-3-thione

This is obtained from commercial 1-phenyl-2-butanone (Aldrich, 98% pure)by applying the method of Thuillier and Vialle (Bull. Soc. Chim. Fr,1962, 2187).

1,1-Bis(methylthio)-2-phenyl-1-penten-3-one, obtained by condensation ofcarbon disulphide with the above ketone in the presence of sodiumtert-amylate followed by methylation with methyl iodide (Yld=80%), istreated with phosphorus pentasulphide in xylene solution. Thedithiolethione is isolated according to the usual method (cooling,washing with sodium hydroxide solution and then with water toneutrality, drying over sodium sulphate, concentration andchromatography). Yield of the sulphuration=70%.

The product is in the form of orange-coloured crystals; m.p. 64° C.(benzene).

¹ H NMR (CDCl₃, δ ppm/TMS): 1.35 (t, 3H); 2.65 (q, 2H); 7.25 to 7.65 (m,5H).

Example B Preparation of 5-propyl-1,2-dithiole-3-thione

This is obtained by sulphuration of ethyl butyrylacetate (Aldrichcommercial product, 98% pure) according to the process of L. Legrand andN. Lozac'h (Bull. Soc. Chim. Fr, 195, 79).

A suspension of 0.061 mol of phosphorus pentasulphide and 0.26 mol ofsulphur in 250 cm³ of dry xylene is brought to reflux. A solution of0.13 mol of ethyl butyrylacetate in 30 cm³ of dry xylene is addeddropwise. The mixture is left under reflux for 15 to 30 minutes. Aftercooling, the xylene solution is washed with dilute sodium hydroxidesolution and then with water to neutrality. After drying over sodiumsulphate, the 5-propyl-1,2-dithiole-3-thione is purified bychromatography on activated neutral alumina (Yld=70%); it is a dark redliquid. ¹ H NMR (CDCl₃, δ ppm/TMS): 1.10 (t, 3H); 1.87 (m, 2H) 2.83 (t,2H); 7.23 (s, 1H).

The characteristics of dithiolethiones of formula III are given below.

    __________________________________________________________________________                                                     Crystal-                                                                      lisation                                            R.sub.1                                                                            R.sub.2  Colour M.p. °C.                                                                    solvent                      __________________________________________________________________________    5-Ethyl-4-phenyl-1,2-dithiole-3-thione                                                               C.sub.6 H.sub.5                                                                    CH.sub.3 Orange 64   Benzene                                                           crystals                                 4-Methoxy-5-methyl-1,2-dithiole-3-thione                                                             CH.sub.3 O                                                                         H        Yellow 51   Petroleum                                                         crystals    ether                        5-Isobutyl-4-methyl-1,2-dithiole-3-thione                                                            CH.sub.3                                                                           CH.sub.3CHCH.sub.3                                                                     Orange-                                                                              50   Petroleum                                                         yellow      ether                                                             crystals                                 4-Phenyl-5-(2-phenylethyl)-1,2-dithiole-3-thione                                                     C.sub.6 H.sub.5                                                                    C.sub.6 H.sub.5 CH.sub.2                                                               Orange-red                                                                           101  Methanol                                                          crystals                                 5-Benzyl-4-ethoxycarbonyl-1,2-dithiole-3-thione                                                      COOEt                                                                              C.sub.6 H.sub.5                                                                        Light brown                                                                          37   Benzene                                                           crystals                                 5-(α-thienylmethyl)-1,2-dithiole-3-thione                                                      H                                                                                   ##STR31##                                                                             Yellow crystals                                                                      98   Cyclo- hexane                4-Benzyl-5-ethyl-1,2-dithiole-3-thione                                                               C.sub.6 H.sub.5 CH.sub.2                                                           CH.sub.3 Yellow                                                                        liquid*                                  5-Propyl-1,2-dithiole-3-thione                                                                       H    CH.sub.3 CH.sub.2                                                                      Red liquid*                              __________________________________________________________________________     *Liquids not distilled                                                   

It was found that the compounds of formula I possessed advantageouspharmacological properties and could be used in therapy.

The compounds of formulae II and VI have substantial antimicrobialactivity;

The compounds of formula II have significant action on calcium andpotassium channels and, as a result, exhibit, inter alia, activity inthe cardiovascular field and in gastroenterology, as well as an actionon the central nervous system and the respiratory system.

In addition, some of them are antihypertensives or β-blockers and areactive with respect to the respiratory system, more especially attracheal level, and have antiallergic properties due to theirbroncho-relaxant action.

The products of the invention possess, considering all groupscollectively, platelet aggregation-inhibitory properties.

In addition, the compounds of formula I have been shown to befree-radical scavenger agents. They can, as a result, find applicationas anti-inflammatory, anti-atheroma and anti-ischaemic agents, forcombatting ageing, for protecting the liver, as a radioprotective andanticarcinogenic agent, in gasteoenterology, at cardiovascular,respiratory and central level, and more generally as antioxidants.

Results of toxicological studies performed in mice are given below.

Furthermore, the compounds of formula I exert an effect on glutathioneand glutathione-dependent enzymes, and give rise to correspondingtherapeutic properties (detoxification , anticarcinogenic power). Inaddition, the compounds of formula I were shown to be immunomodulatory.

    ______________________________________                                                        Toxicity in mg/kg                                             R.sub.1  R.sub.2                                                                              Code      ip (mouse)                                                                            po (mouse)                                  ______________________________________                                        TOXICITY                                                                      OXIMES OF FORMULA II                                                          --(CH.sub.2).sub.3 --                                                                     11        200       300                                           H        H      3          50     100                                         H        C.sub.6 H.sub.5                                                                      4         100     300                                         C.sub.2 H.sub.5                                                                        CH.sub.3                                                                             9         >100    300                                         H        C.sub.2 H.sub.5                                                                      17        100     300                                         OCH.sub.3                                                                              H      5          50      50                                         TOXICITY                                                                      KETONES OF FORMULA VI                                                         CH.sub.3 H      41        100      100                                        CH.sub.3 CH.sub.3                                                                             44        300     >300                                        C.sub.2 H.sub.5                                                                        CH.sub.3                                                                             50        100     >300                                        ______________________________________                                    

The therapeutic compositions according to the invention may beadministered to man or animals orally or parenterally.

They can be in the form of solid, semi-solid or liquid preparations. Asan example, tablets, hard gelatin capsules, suppositories and injectablesolutions or suspensions may be mentioned, as well as retard forms andslow-release implanted forms.

In these compositions, the active principle is generally mixed with oneor more customary, pharmaceutically acceptable excipients which are wellknown to a person skilled in the art.

The amount of active principle administered naturally depends on thepatient who is being treated, the administration route and the severityof the disease.

We claim:
 1. Compounds of formula ##STR32## in which R₁ and R₂ arechosen, independently of one another, from hydrogen, a halogen, a nitrogroup, a nitroso group, a thiocyano group, a C₁ -C₆ alkyl group, a C₂-C₆ alkenyl group, an aryl group, an aryl (C₁ -C₆ alkyl) group, anaryl(C₂ -C₆ alkenyl) group, a carboxyl group, a (C₁ -C₆ alkyl)carbonylgroup, an arylcarbonyl group, a (C₁ -C₆ alkoxy)carbonyl group, a (C₁ -C₆alkoxy)carbonyl(C₁ -C₆ alkyl) group, a C₁ -C₆ alkoxy group, atrifluoromethyl group, an amino group, a di(C₁ -C₆ alkyl)-amino(C₁ -C₆alkyl) group, an acylamino group of formula --NHCOC_(n) H_(2n+1) with nfrom 0 to 6, a group --NH--CSC_(n) H_(2n+1) with n from 0 to 6, aterpenyl group, a cyano group, a C₂ -C₆ alkynyl group, a C₂ -C₆ alkynylgroup substituted with a C₁ -C₆ alkyl or an aryl group, a hydroxy(C₁ -C₆alkyl) group, a (C₁ -C₆ acyl)-oxy(C₁ -C₆ alkyl) group, a (C₁ -C.sub. 6alkyl)thio group and an arylthio group,or alternatively R₁ and R₂together form a mono- or polycyclic C₂ -C₂₀ alkylene group optionallycomprising one or more hetero atoms, with the exception of the2,2-dimethyltrimethylene group, or a C₃ -C₁₂ cycloalkylene group. 2.Compounds of formula ##STR33## in which R₁ and R₂ are chosen,independently of one another, from hydrogen, a halogen; a nitro group, anitroso group, a thiocyano group, a C₁ -C₆ alkyl group, a C₂ -C₆ alkenylgroup, an aryl group, an aryl(C₁ -C₆ alkyl) group, an aryl(C₂ -C₆alkenyl) group, a carboxyl group, a (C₁ -C₆ alkyl)carbonyl group, anarylcarbonyl group, a (C₁ -C₆ alkoxy)carbonyl group, a (C₁ -C₆alkoxy)carbonyl(C₁ -C₆ alkyl) group, a C₁ -C₆ alkoxy group, atrifluoromethyl group, an amino group, a di(C₁ -C₆ alkyl)-amino(C₁ -C₆alkyl) group, an acylamino group of formula --NHCOC_(n) H_(2n+1) with nfrom 0 to 6, a group --NH--CSC_(n) H_(2n+1) with n from 0 to 6, aterpenyl group, a cyano group, a C₂ -C₆ alkynyl group, a C₂ -C₆ alkynylgroup substituted with a C₁ -C₆ alkyl or an aryl group, a hydroxy(C₁ -C₆alkyl) group, a (C₁ -C₆ acyl)-oxy(C₁ -C₆ alkyl) group, a (C₁ -C₆alkyl)thio group and an arylthio group,or alternatively R₁ and R₂together form a mono- or polycyclic C₂ -C₂₀ alkylene group optionallycomprising one or more hetero atoms, with the exception of the2,2-dimethyltrimethylene group, or a C₃ -C₁₂ cycloalkylene group; andR'₃ is chosen from a C₁ -C₆ alkyl group, a C₁ -C₆ alkyl groupsubstituted with one or more groups chosen from hydroxyl, amino, chloroand C₁ -C₄ alkoxy groups and an aryl(C₁ -C₆ alkyl) group.
 3. Compoundsof formula ##STR34## in which R₁ and R₂ are chosen, independently of oneanother, from hydrogen, a halogen, a nitro group, a nitroso group, athiocyano group, a C₁ -C₆ alkyl group, a C₂ -C₆ alkenyl group, an arylgroup, an aryl(C₁ -C₆ alkyl) group, an aryl(C₂ -C₆ alkenyl) group, acarboxyl group, a (C₁ -C₆ alkyl)carbonyl group, an arylcarbonyl group, a(C₁ -C₆ alkoxy)carbonyl group, a (C₁ -C₆ alkoxy)carbonyl(C₁ -C₆ alkyl)group, a C₁ -C₆ alkoxy group, a trifluoromethyl group, an amino group, adi(C₁ -C₆ alkyl)-amino(C₁ -C₆ alkyl) group, an acylamino group offormula --NHCOC_(n) H_(2n+1) with n from 0 to 6, a group --NH--CSC_(n)H_(2n+1) with n from 0 to 6, a terpenyl group, a cyano group, a C₂ -C₆alkynyl group, a C₂ -C₆ alkynyl group substituted with a C₁ -C₆ alkyl oran aryl group, a hydroxy(C₁ -C₆ alkyl) group, a (C₁ -C₆ acyl)-oxy(C₁ -C₆alkyl) group, a (C₁ -C₆ alkyl)thio group and an arylthio group,oralternatively R₁ and R₂ together form a mono- or polycyclic C₂ -C₂₀alkylene group optionally comprising one or more hetero atoms, with theexception of the 2,2-dimethyltrimethylene group, or a C₃ -C₁₂cycloalkylene group; and R"₃ is chosen from a hydrogen atom, a C₁ -C₆alkyl group, a C₁ -C₆ alkyl group substituted with one or more groupschosen from hydroxyl, amino, chloro and C₁ -C₄ alkoxy groups and anaryl(C₁ -C₆ alkyl) group.
 4. Pharmaceutical composition comprising, asactive principle, a compound according to claim
 1. 5. Pharmaceuticalcomposition comprising, as active principle, a compound according toclaim
 2. 6. Pharmaceutical composition comprising, as active principle,a compound according to claim 3.